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Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis

2016; Nature Portfolio; Volume: 13; Issue: 1 Linguagem: Inglês

10.1038/nchembio.2238

1552-4469

Valerian E. Kagan, Gaowei Mao, Feng Qu, José Pedro Friedmann Angeli, Sebastian Doll, Claudette M. St. Croix, Haider H. Dar, Bing Liu, Vladimir A. Tyurin, Vladimir B. Ritov, Alexandr A. Kapralov, Andrew A. Amoscato, Jianfei Jiang, Tamil S. Anthonymuthu, Dariush Mohammadyani, Qin Yang, Bettina Proneth, Judith Klein‐Seetharaman, Simon C. Watkins, İvet Bahar, Joel S. Greenberger, Rama K. Mallampalli, Brent R. Stockwell, Yulia Y. Tyurina, Marcus Conrad, Hülya Bayır,

interferon and immune responses

Arachidonyl and adrenoyl PE phospholipids generated by ACSL4, an acyl-CoA synthase, are doubly or triply oxidized by lipoxygenases and other iron-containing sources of oxidation to promote ferroptotic cell death. Enigmatic lipid peroxidation products have been claimed as the proximate executioners of ferroptosis—a specialized death program triggered by insufficiency of glutathione peroxidase 4 (GPX4). Using quantitative redox lipidomics, reverse genetics, bioinformatics and systems biology, we discovered that ferroptosis involves a highly organized oxygenation center, wherein oxidation in endoplasmic-reticulum-associated compartments occurs on only one class of phospholipids (phosphatidylethanolamines (PEs)) and is specific toward two fatty acyls—arachidonoyl (AA) and adrenoyl (AdA). Suppression of AA or AdA esterification into PE by genetic or pharmacological inhibition of acyl-CoA synthase 4 (ACSL4) acts as a specific antiferroptotic rescue pathway. Lipoxygenase (LOX) generates doubly and triply-oxygenated (15-hydroperoxy)-diacylated PE species, which act as death signals, and tocopherols and tocotrienols (vitamin E) suppress LOX and protect against ferroptosis, suggesting a homeostatic physiological role for vitamin E. This oxidative PE death pathway may also represent a target for drug discovery.